N2 -substituted-L-arginine derivatives and the pharmaceutically acceptable acid addition salts thereof

ABSTRACT

N 2  -substituted-L-arginine esters and amides, and the pharmaceutically acceptable acid addition salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of application Ser. No. 671,436 Mar. 29, 1976, which in turn was a divisional of application Ser. NO. 622,390 filed Oct. 14, 1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N² -substituted-L-arginine derivatives and the pharmaceutically acceptable acid addition salts thereof, which are of special value in view of their outstanding antithrombotic properties.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improved agents for the treatment of thrombosis. Of these, N² -(p-tolylsulfonyl)-L-argining esters are known to be effective in dissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).

However, there is a continuing need for a highly specific inhibitor on thrombin for the control of thrombosis. Accordingly, we have discovered novel N² -substituted-L-arginine derivatives which exhibit antithrombotic activity.

SUMMARY OF THE INVENTION

In summary, the compounds of this invention can be represented by the formula (I): ##STR1## wherein R is selected from the group consisting of (1)--OR₁, wherein R₁ is selected from the group consisting of C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl, C₁ -C₁₀ haloalkyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl and C₇ -C₁₅ aralkyl; ##STR2## wherein R₂ and R₃ are selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₅ aralkyl, and C₁ -C₁₀ alkyl substituted with a group selected from C₁ -C₁₀ alkoxy, C₂ -C₁₀ alkoxycarbonyl and carboxy; and (3)--N Z, wherein Z is a divalent group which consists of two or more groups selected from methylene --CH₂ -- and monosubstituted ##STR3## (wherein R₄ is selected from the group consisting of C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy); and zero or one of more than one group selected from oxy --O--, thio --S--, alkyl substituted ##STR4## (wherein R₅ is C₁ -C₁₀ alkyl) and acyl substituted ##STR5## (wherein R₆ is C₁ -C₁₀ alkyl), which are combined in an arbitrary order, the number of the combined groups being up to 20; and R' is selected from the group consisting of ##STR6## wherein R" and R'" when considered separately are C₁ -C₁₀ alkyl, or R" and R'" when taken together are C₁ -C₁₀ alkylene; ##STR7## wherein R'" is C₁ -C₁₀ alkoxy; ##STR8## Also encompassed within this invention are pharmaceutically acceptable acid addition salts thereof.

This invention also relates to a method for inhibiting activity and suppressing activation of thrombin in vivo, which comprises introducing into a living body a pharmaceutically effective amount of an N² -substituted-L-arginine ester or amide or the pharmaceutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As summarized above, this invention relates to a group of N² -substituted-L-arginine esters and amides of the formula (I): ##STR9## wherein R is represented by the formula (1)--OR₁, (2) ##STR10## or (3)--N Z, each of which will be described below in detail. 1. In case where R is --OR₁

R₁ is selected from the group consisting of C₁ -C₁₀ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like; C₃ -C₁₀ cycloalkyl such as cyclopropyl, cyclohexyl or the like; C₁ -C₁₀ haloalkyl such as 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl or the like; C₂ -C₁₀ alkoxyalkyl such as 2-methoxyethyl, 2-ethoxyethyl or the like; C₂ -C₁₀ alkenyl such as allyl, 2-butenyl or the like; C₂ -C₁₀ alkynyl such as 3-butynyl or the like; and C₇ -C₁₅ aralkyl such as benzyl, phenethyl or the like.

2. In case where R is ##STR11##

R₂ and R₃ are selected from the group consisting of hydrogen; C₁ -C₁₀ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl or the like; C₇ -C₁₅ aralkyl such as benzyl, phenethyl, 3-phenylpropyl or the like; and C₁ -C₁₀ alkyl substituted with a group selected from C₁ -C₁₀ alkoxy, C₂ -C₁₀ alkoxycarbonyl and carboxy such as 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-ethoxy-carbonylpropyl, carboxymethyl, 2-carboxyethyl or the like.

3. In case where R = --N Z

Z is a divalent group which consists of two or more groups selected from methylene --CH₂ -- and monosubstituted ##STR12## (wherein R₄ is selected from the group consisting of C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy), and zero or one or more than one group selected from oxy --O--, thio --S--, alkyl substituted ##STR13## (wherein R₅ is C₁ -C₁₀ alkyl) and acyl substituted ##STR14## (wherein R₆ is C₁ -C₁₀ alkyl), which are combined in an arbitrary order, the number of the combined groups being normally up to 20. More particularly, R includes 1-polymethyleneiminyl groups or the derivatives thereof, such as 1-aziridinyl, 1-azetidinyl, 3-methoxy-1-azetidinyl, 3-ethoxy-1-azetidinyl, 1-pyrrolidinyl, piperidino, 4-methylpiperidino, 4-ethylpiperidino, 4-propylpiperidino, 4-isopropylpiperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methoxypiperidino, 1-hexamethyleneiminyl, 1-octamethyleneiminyl, and the like; an oxazole or thiazole series such as 3-oxazolidinyl, 3-thiazolidinyl, and the like; an isoxazole or isothiazole series such as 2-isoxazolidinyl, 2-isothiazolidinyl, and the like; an oxazine series such as morpholino, 2,6-dimethylmorpholino, tetrahydro-1,3-oxazin-3-yl, and the like; a thiazine series such as tetrahydro-1,4-thiazin-4-yl, and the like; 4-methyl-1-piperazinyl, 4-acetyl-1-piperazinyl, and the like.

The preferred R groups are the following:

1. In case where R is --OR₁

C₁ -C₈ alkoxy, cyclohexyloxy, C₂ -C₆ omega-chloroalkoxy, C₂ -C₆ omega-alkoxyalkoxy, C₃ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy, C₇ -C₉ aralkyloxy

2. In case where R is ##STR15##

C₁ -C₉ alkylamino, C₂ -C₆ omega-alkoxyalkylamino, C₃ -C₈ omega-alkoxycarbonylalkylamino, C₇ -C₁₀ aralkylamino, C₂ -C₁₀ dialkylamino

3. In case where R is --N Z

C₃ -C₁₀ N,N-polymethyleneiminyl; C₃ -C₁₀ N,N-polymethyleneiminyl substituted with a group selected from C₁ -C₅ alkyl and C₁ -C₅ alkoxy; tetrahydro-1, n-oxazin-n-yl (n=2, 3 or 4); tetrahydro-1, n-thiazin-n-yl (n=2,3 or 4); 1-piperazinyl substituted with a group selected from C₁ -C₅ alkyl and C₁ -C₅ acyl

The most preferred R groups are the following:

1. In case where R is --OR₁

propoxy, butoxy, hexyloxy, cyclohexyloxy, 3-chloropropoxy, 2-methoxyethoxy, 2-butenyloxy, 3-butynyloxy, benzyloxy

2. In case where R is ##STR16##

butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, benzylamino, N-methyl-N-butylamino

3. In case where R is --N Z

piperidino, hexamethyleneiminyl, 4-methylpiperidino, 4-ethylpiperidino, 4-methoxypiperidino, morpholino, tetrahydro-1,4-thiazin-4-yl, 4-methyl-1-piperazinyl, 4-acetyl-1-piperazinyl

In the above formula (I), R' is a member selected from the group consisting of (a) substituted naphthyl ##STR17## wherein R" and R'" when considered separately are respectively C₁ -C₁₀ (preferably C₁ -C₅) alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the like; or R" and R'" when taken together are C₁ -C₁₀ (preferably C₁ -C₅) alkylene such as methylene, ethylene, trimethylene or the like; the alkoxy (--OR", --OR'") or the alkylenedioxy (--OR"--R'"O--) group and the sulfonyl group may be located at any of the 1- to 8- position of the naphthalene nucleus; normally, the sulfonyl group is located at 1- or 2-position, and the alkylenedioxy group is a 6,7-alkylenedioxy group; (b) 6-chromanyl ##STR18## (c) 1,4-benzodioxan-6-yl ##STR19## (d) 2H-3,4-dihydro-1,5-benzodioxepin-7-yl ##STR20## (e) derivatives of (d) having a substituent at the 3-position ##STR21## wherein R"" is C₁ -C₁₀ (preferably C₁ -C₅) alkoxy, (f) 2-dibenzofuranyl ##STR22## (g) 4-dibenzofuranyl (h) 2-xanthenyl and (i) dibenzo-p-dioxin-2-yl Typical of the R' group are the following: ##STR23##

Illustrative of the typical N² -substituted-L-arginine esters and amides of this invention are the following:

1. In the case of the ester derivatives

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine propyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine benzyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine 3-chloropropyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine 2-methoxyethyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine 3-butynyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine 2-butenyl ester

2. In the case of the amide derivatives wherein R is ##STR24## N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-benzyl-L-argininamide

N² -(2-xanthenesulfonyl)-N-methyl-N-butyl-L-argininamide

3. In the case of the amide derivatives wherein R is --N Z

4-methyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]hexamethyleneimine

4-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]morpholine

4-methoxy-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-methyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl]piperidine

4-methyl-1-[N² -(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(3-methoxy-(2H-3,4-dihydro-1,5-benzodioxepin)-7-sulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(2-xanthenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(2-dibenzofuransulfonyl)-L-arginyl] piperidine

4-ethyl-1-[N² -(4-dibenzofuransulfonyl)-L-arginyl] piperidine

4-ethyl-1-[N² -(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl] piperidine

1-[N² -(4-dibenzofuransulfonyl)-L-arginyl]hexamethyleneimine

The following compounds are most preferred due to their high level of antithrombotic activity.

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide

4-methyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-methoxy-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-methyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(2-xanthenesulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(4-dibenzofuransulfonyl)-L-arginyl]piperidine

4-ethyl-1-[N² -(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl] piperidine

The pharmaceutically acceptable acid addition salts of the above compounds are of course also included within the scope of this invention.

The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not to be construed as limiting the scope of the invention. These typical compounds are highly potent in their antithrombotic activity. For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. Successful preparation of these compounds is possible by way of several synthetic routes which are outlined below.

1. PREPARATION OF N² -SUBSTITUTED-L-ARGININE ESTERS a. Esterification of an N² -substituted-L-arginine

i. Reaction of an N² -substituted-L-arginine and an alcohol

This process may be illustrated as follows: ##STR25## In the above formulas, R is --OR₁, in which R₁ is as defined herein above, and R' is as defined herein above.

The N² -substituted-L-arginine ester (I) is prepared by esterifying an N² -substituted-L-arginine (II) with an alcohol (III).

The esterification can be effected by reacting the N² -substituted-L-arginine with at least 5 equivalents of the alcohol in the presence of at least an equimolar amount of an acid catalyst such as hydrogen chloride, sulfuric acid, toluenesulfonic acid or the like.

The reaction is generally carried out without an added solvent or in a suitable reaction-inert solvent at a temperature of 0° C to the boiling temperature of the alcohol or the solvent for a period of 10 minutes to 15 hours. The preferred solvents are those which form an azeotropic mixture with water and facilitates the removal of water formed during the reaction.

Examples of such solvents are benzene, toluene, xylene, cyclohexane, carbon tetrachloride and dichloromethane.

After the reaction is complete, the alcohol and/or the solvent is distilled off to give the N² -substituted-L-arginine ester (I) or an acid addition salt thereof, which can be purified by recrystallization from a combination of solvents such as ethyl ether, alcohols and acetone, or by reprecipitation by adding ether to the alcohol solution thereof. The acid addition salt of the N² -substituted-L-arginine ester can be easily converted to the corresponding ester by adjusting the pH of the solution.

ii. Reaction of an N² -substituted-L-arginine, an alcohol and a thionyl halide.

The N² -substituted-L-arginine ester (I) can be prepared by reacting an N² -substituted-L-arginine (II), an alcohol (III) and a thionyl halide such as thionyl chloride or thionyl bromide.

The thionyl halide is preferably used in an amount not less than 2 moles per mole of the N² -substituted-L-arginine.

The other reaction conditions such as reaction temperature, reaction time, amount of the alcohol to be used; and the procedures of separation and purification of the product are as described above in the esterification with an acid catalyst.

According to this method, the product is usually a halogeno acid salt of the N² -substituted-L-arginine ester.

The N² -substituted-L-arginine (II) can be esterified by many other procedures. The N² -substituted-L-arginines (II) starting materials are readily obtained by reacting arginine and a sulfonyl halide (preferably a chloride) of the formula (IV):

    r'so.sub.2 x                                               (iv)

wherein R' is as defined herein above and X is halogen, in the presence of a base such as K₂ CO₃, KOH, NaOH, triethylamine or pyridine.

b. Condensation of an L-arginine ester with a sulfonyl halide

This process may be illustrated as follows: ##STR26## In the above formulas, R is --OR₁ wherein R₁ is as defined herein above; R' is as defined herein above; and X is halogen.

The N² -substituted-L-arginine ester (I) is prepared by the condensation of an L-arginine ester (V) with a substantially equimolar amount of a sulfonyl halide (IV), preferably a chloride.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of an excess of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, potassium carbonate), at a temperature of 0° C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.

The preferred solvents for the condensation include dichloromethane, diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water, and the solvent is removed by such standard means as evaporation under reduced pressure to give the N² -substituted-L-arginine ester (I), which can be purified by trituration or recrystallization from a suitable solvent, such as diethyl ether-tetrahydrofuran, diethyl ethermethanol and water-methanol, or may be chromatographed on silica gel.

The L-arginine ester (V) starting materials are most generally prepared by reacting L-arginine with an alcohol in the presence of an acid catalyst.

2. Preparation of N² -substituted-L-argininamides a. Condensation of an L-argininamide with a sulfonyl halide

This process may be illustrated as follows: ##STR27## In the above formulas, R is ##STR28## or --N Z wherein R₂, R₃ and Z are as defined herein above; R' is as defined herein above; and X is halogen. The N² -substituted-L-argininamide (I) is prepared by condensing an L-argininamide (V) with a substantially equimolar amount of a sulfonyl halide (IV), preferably a chloride, in the presence of a base.

The reaction conditions are the same as those described in the Process (1) (b) (condensation of an L-arginine ester with a sulfonyl halide).

The L-argininamides (V) starting materials required for the condensation reaction can be prepared by protecting the guanidino and α-amino group of the arginine via nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation, tert-butoxycarbonylation or tritylation and then condensing the formed N^(G) -substituted-N² -substituted-L-arginine with a corresponding amine by such a conventional process as the acid chloride method, azide method, mixed anhydride method, activated ester method or carbodiimide method, and thereafter selectively removing the protective group.

b. Removal of the N^(G) -substituent from an N^(G) -substituted-N² -substituted-L-argininamide

This process may be illustrated as follows: ##STR29## In the above formulas, R is ##STR30## or --N Z, wherein R₂, R₃ and Z are as defined herein above; R' is as defined herein above; X is halogen; Y" is a protective group for the amino group, such as benzyloxycarbonyl or tert-butoxycarbonyl; and Y and Y' are hydrogen and protective groups for the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl or the like.

At least one of Y and Y' is a protective group for the guanidino group.

The N² -substituted-L-argininamide (I) is prepared by removing the N^(G) -substituent from an N^(G) -substituted-N² -substituted-L-argininamide (IX) by means of acidolysis or hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G) -substituted-N² -substituted-L-argininamide (IX) and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol) or acetic acid at a temperature of -10° C to 100° C, and preferably at room temperature for a period of 10 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.

Because of the use of the excess acid, the products are generally the acid addition salts of the N² -substituted-L-argininamides (I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished by the hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activating catalyst, e.g., Raney nickel, palladium, or platinum, in a hydrogen atmosphere at a temperature of 0° C to the boiling temperature of the solvent for a period of 2 hours to 120 hours. The hydrogen pressure is not critical, and atmospheric pressure is sufficient.

The N² -substituted-L-argininamides (I) are isolated by filtration of the catalyst followed by evaporation of the solvent.

The N² -substituted-L-argininamides can be purified in the same manner as described above.

The N^(G) -substituted-N² -substituted-L-argininamides (IX) starting materials can be prepared by condensing an N^(G) -substituted-N² -substituted-L-arginine (VI) (generally the N² -substituent is a protective group for the amino group, such as benzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a corresponding amine (III) via the azide method, mixed anhydride method, activated ester method, carbodiimide method or the like, selectively removing only the N² -substituent of an N^(G) -substituted-N² -substituted-L-argininamide (VII) by means of a catalytic hydrogenolysis or acidolysis, and then condensing the thus obtained N^(G) -substituted-L-argininamide (VIII) with a sulfonyl halide (IV), preferably a chloride in the presence of a base in a solvent. These reaction conditions are as described above in the condensation of an L-argininamide with a sulfonyl halide, and the removal of the N^(G) -substituent from an N^(G) -substituted-N² -substituted-L-argininamide.

c. Condensation of an N² -substituted-L-arginyl halide with an amine

This process may be illustrated as follows: ##STR31## In the above formulas, R is ##STR32## or --N Z, wherein R₂, R₃ and Z are as defined herein above; R' is as defined herein above; and X is halogen. The N² -substituted-L-argininamide (I) is prepared by the condensation of an N² -substituted-L-arginyl halide (X), preferably a chloride with at least an equimolar amount of an amine (III). The condensation reaction can be carried out without an added solvent. However, satisfactory results will be obtained with the use of a solvent such as basic solvents (dimethylformamide, dimethylacetamide, etc.) or halogenated solvents (chloroform, dichloromethane, etc.)

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -substituted-L-arginyl halide (X). Preferred condensation reaction temperatures are in the range of from -10° C to room temperature. The reaction time is not critical, but varies with the amine (III) employed. In general, a period of from 5 minutes to 10 hours is operable.

The obtained N² -substituted-L-argininamide can be isolated and purified in the same manner as described above.

The N² -substituted-L-arginyl halide (X) starting materials required for the condensation reaction can be prepared by reacting the N² -substituted-L-arginine (II) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorous pentachloride or phosphorus tribromide. The halogenation can be carried out with or without an added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary from about 5 to 100 times the weight of the N² -substituted-L-arginine. Preferred reaction temperatures are in the range of -10° C to room temperature. The reaction time is not critical, but varies with the halogenating agent and reaction temperature. In general, a period of 15 minutes to 5 hours is operable.

d. Guanidylation of an N² -substituted-L-ornithinamide or an acid addition salt thereof

This process may be illustrated as follows: ##STR33## In the above formulas, R is ##STR34## or --N Z, wherein R₂, R₃ and Z are as defined herein above; and R' is as defined herein above.

The N² -substituted-L-argininamide (I) is prepared by guanidylating an N² -substituted-L-ornithinamide (XI) with an ordinary guanidylating agents such as an O-alkylisourea, S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or carbodiimide. The preferred guanidylating agents are the O-alkylisourea and the S-alkylisothiourea.

The guanidylation of the N² -substituted-L-ornithinamide (XI) with the O-alkylisourea or S-alkylisothiourea is generally effected in a solvent in the presence of a base at a temperature of from 0° C to the boiling temperature of the solvent for a period of from 30 minutes to 50 hours.

Examples of the preferred base are triethylamine, pyridine, sodium hydroxide and sodium methoxide. The base is used in an amount of 0.01 to 0.1 equivalent to the N² -substituted-L-ornithinamide. Examples of the preferred solvent are water, water-ethanol and water-dioxane. After the reaction is complete, the N² -substituted-L-argininamide (I) is isolated by evaporation of the solvent followed by removal of the excess base and the formed salt by a water wash.

e. Reaction of an N² -substituted-L-arginine ester and a primary amine

This process may be illustrated as follows: ##STR35## In the above formulas, R₂ and R' are as defined herein above; and R₇ is C₁ -C₁₀ alkyl.

The N² -substituted-L-argininamide represented by the formula (XIV) can be prepared by the reaction of an N² -substituted-L-arginine ester (XII) and about 2 to 10 equivalents of a primary amine (XIII). The reaction is generally carried out without an added solvent or in a solvent such as an alcohol (methanol, ethanol), an ether (ethyl ether, tetrahydrofuran), a hydrocarbon (benzene, toluene), a halogenated hydrocarbon (chloroform, dichloromethane) or water at room temperature for a period of several hours to several days. In order to accelerate to reaction, the reaction mixture may be heated to a temperature of up to the boiling point of the amine or the solvent. Alternatively, a basic catalyst such as sodium methoxide or pyridine may be added to the reaction mixture.

After the reaction is complete, the formed N² -substituted-L-argininamide (XIV) is isolated by filtration or by evaporation of the excess amine and/or the solvent, washed with water, and then purified by recrystallization from a suitable solvent such as water-methanol.

The N² -substituted-L-arginine esters or amides (I) of this invention form acid addition salts with any of a variety of inorganic and organic acids. The product of the reactions described above can be isolated in the free form or in the form of acid addition salts. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. Likewise, treatment of the acid addition salts with a base result in a regeneration of the free amide or ester.

As stated above, the N² -substituted-L-arginine esters and amides, and the salts thereof of this invention are characterized by highly specific inhibitory activity against thrombin, and therefore, these compounds are useful in the determination of thrombin in blood as diagnostic reagents, and/or for the medical control or prevention of thrombosis. The antithrombotic activities of the N² -substituted-L-arginine esters and amides of this invention were compared with that of a known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining the fibrinogen coagulation time. The measurement of the fibrinogen coagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied by Armour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with 0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solution in the same buffer, and 0.1 ml of a thrombin solution (5 units/ml) supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutions in an ice bath. Immediately after mixing, the reaction mixture was transferred from the ice bath to a bath maintained at 25° C. Coagulation times were taken as the period between the time of transference to the 25° C bath and the time of the first appearance of fibrin threads. In the cases where no drug samples were added, the coagulation time was 50-55 seconds.

The experimental results are summarized in TABLE 1. The term "concentration required to prolong the coagulation time by a factor of two" is the concentration of an active ingredient required to prolong the normal coagulation time of 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factor of two for the known antithrombotic agent, N² -(p-tolylsulfonyl)-L-arginine methyl ester, was 1,000 μM.

The inhibitors are shown in TABLE 1 by indicating R and R' in the formula (I) and the addition moiety.

When a solution containing an N² -substituted-L-arginine ester or amide of this invention was administered intravenously into animal bodies, the high antithrombotic activity in the circulating blood was maintained for from one to three hours. The half-life for decay of the antithrombotic compounds of this invention in circulating blood was shown to be approximately 30 minutes; the physiological conditions of the host animals (rat, rabbit, dog and chimpanzee) were well maintained. The experimental decrease of fibrinogen in animals caused by infusion of thrombin was satisfactorily controlled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by oral administration of substances of formula (I) in mice (male, 20 g) range from about 1,000 to 10,000 milligrams per kilogram of body weight.

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharamceutical practice. For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents.

Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kg orally per day.

Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1

1.0 g (0.0018 mole) of 4-ethyl-1-[N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine were added 5.7 g (0.0053 mole) of anisole and 3 ml of hydrogen fluoride while cooling with Dry-ice/acetone, and the mixture was stirred for 30 minutes in an ice bath. The anisole and the excess hydrogen fluoride were evaporated at reduced pressure with cooling to afford an oily product, which wa slurried with 100 ml of dry ethyl ether. The ether layer was separated by decantation, and the obtained powder was dissolved in methanol, reprecipitaed with ethyl ether, and then filtered to give 4-ethyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine hydrofluoride in the powder form in a yield of 75%.

    ______________________________________                                         Elemental analysis: as C.sub.25 H.sub.37 O.sub.5 N.sub.5 S . HF                             C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        55.64     7.10    12.98                                     Found   (%)        55.50     7.12    12.87                                     ______________________________________                                    

EXAMPLE 2

Into a suspension of 1.0 g(0.00186 mole) of 4-[N^(G) -nitro-N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]morpholine and 0.1 g of palladium black in 30 ml of ethanol and 10 ml of acetic acid was passed hydrogen gas for 60 hours at room temperature. Upon completion of the reaction, the catalyst was filtered off, and the solvent was evaporated under reduced pressure to give a viscous oily residue, which was taken up in methanol and reprecipitated with ether to afford 4-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl] morpholine acetate in the powder form in a yield of 82%.

    ______________________________________                                         Elemental analysis: as C.sub.22 H.sub.31 O.sub.6 N.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        52.07     6.37    12.65                                     Found   (%)        51.99     6.28    12.41                                     ______________________________________                                    

EXAMPLE 3

Into a suspension of 2.9 g (0.0027 mole) of N^(G),N^(G) -dibenzyloxycarbonyl-N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-butyl-L-argininamide and 20% palladium-carbon in 50 ml of ethanol and 10 ml of acetic acid was passed hydrogen gas for 10 hours at room temperature. Upon completion of the reaction, the catalyst was filtered off, and the solvent was evaporated under reduced pressure to give an oily residue, which was reprecipitated with methanol-ether to give N-² -(6,7-dimethoxy-2-naphthalensulfonyl)-N-butyl-L-argininamide acetate in the powder form in a yield of 78%.

    ______________________________________                                         Elemental analysis: as C.sub.22 H.sub.33 O.sub.5 N.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        53.42     6.91    12.98                                     Found   (%)        53.61     6.87    12.71                                     ______________________________________                                    

EXAMPLE 4

To 5.0 ml (0.069 mole) of cold thionyl chloride was added with vigorous stirring 1.0 g (0.00236 mole) of N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine, and the reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, 100 ml of dry ether was added to the reaction mixture, and the formed precipitate was collected and washed well with 50 ml of dry ether.

The thus obtained powdery N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride dihydrochloride was added with stirring to a solution of 1.2 g (0.012 mole) of 4-methylpiperidine in 10 ml of chloroform, and the mixture was allowed to stand for 3 hours at room temperature. After the reaction was complete, the solvent and the excess 4-methylpiperidine were distilled under reduced pressure, and the residue was dissolved in 20 ml of chloroform. The chloroform layer was washed well with saturated NaCl aqueous solution and dried over sodium sulfate, and then, the chloroform was distilled under reduced pressure. Addition of 10 ml of acetic acid and 100 ml of dry ether to the residue resulted in deposition of an oily product. The ether was removed by decantation, and the oily product was washed well with dry ether to give powdery 4-methyl-1-[N² -(6,7-dimethoxy-2-naphthalensulfonyl)-L-arginyl]piperidine monoacetate. Yield 1.1 g (84%).

    ______________________________________                                         Elemental analysis: as C.sub.24 H.sub.35 N.sub.5 O.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        55.21     6.95    12.38                                     Found   (%)        55.11     6.74    12.01                                     ______________________________________                                    

EXAMPLE 5

To a suspension of 1.00 g (0.00236 mole) of N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 20 ml of tetrahydrofuran was added little by little 0.98 g (0.0047 mole) of phosphorus pentachloride while cooling with ice water. The mixture was stirred for 1 hour at 0°-5° C, and then, for 2 hours at room temperature. To this reaction mixture was added 100 ml of dry ether, and the supernatant was removed by decantation. The residual oily product was washed with 50 ml of dry ether to give powdery N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride dihydrochloride, which was added with stirring to a solution of 1.31 g (0.015 mole) of N-methyl-N-butylamine in 10 ml of chloroform. Thereafter, following the same procedures as described in Example 1, N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-methyl-N-butyl-L-argininamide monoacetae was obtained. Yield 0.76 g (58%).

    ______________________________________                                         Elemental analysis: as C.sub.23 H.sub.35 N.sub.5 O.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        54.24     7.10    12.65                                     Found   (%)        54.00     7.21    12.46                                     ______________________________________                                    

EXAMPLE 6

To a solution of 1.0 g (0.004 mole) of L-arginine ethyl ester dihydrochloride in 50 ml of dichloromethane and 1.15 g (0.012 mole) of triethylamine was added 1.14 g (0.004 mole) of 4,6-dimethoxy-2-naphthalenesulfonyl chloride with stirring at room temperature. After stirring for 5 hours at room temperature, the reaction mixture was washed with water to remove the formed triethylamine hydrochloride. After the solution was dried over sodium sulfate, the dichloromethane was evaporated under reduced pressure, to give N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester. To this product was added ethyl ether, and then hydrogen chloride was passed. The formed precipitate was filtered to give N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester hydrochloride in the form of a powder.

    ______________________________________                                         Elemental analysis: as C.sub.20 H.sub.29 O.sub.6 N.sub.4 SCl                                C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        49.13     5.97    11.46                                     Found   (%)        48.96     6.15    11.52                                     ______________________________________                                    

EXAMPLE 7

To a suspension of 1.50 g (0.005 mole) of L-arginine butyl ester dihydrochloride in a solution consisting of 1.4 g of potassium carbonate and 10 ml of water, which had been cooled to 0°-5° C, was added dropwise a solution of 1.43 g (0.005 mole) of 6,7-dimethoxy-2-naphthalenesulfonyl chloride in 10 ml of ethyl ether with vigorous stirring over a period of 30 minutes.

The mixture was stirred for further 10 minutes and a viscous deposit was obtained. The solvent was removed by decantation, and the residual deposit was washed with water and ether.

To a suspension of the resulting product in 20 ml of ethyl ether was added 2 g of p-toluenesulfonic acid monohydrate with stirring to yield a crystal, which was filtered and washed several times with ethyl ether to give N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate in 92% yield; m.p. 113°-115° C.

    ______________________________________                                         Elemental analysis: as C.sub.29 H.sub.40 O.sub.9 N.sub.4 S.sub.2                            C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        53.36     6.18    8.59                                      Found   (%)        53.23     6.14    8.70                                      ______________________________________                                    

EXAMPLE 8

To a mixture of 1.00 g (0.0037 mole) of 4-ethyl-1-(L-arginyl) piperidine and 0.61 g (0.0044 mole) of potassium carbonate in 10 ml of water, which had been cooled to 0° C, was added dropwise a solution of 1.25 g (0.0044 mole) of 6,7-dimethoxy-2-naphthalenesulfonyl chloride in 30 ml of dioxane with vigorous stirring over a period of 30 minutes. The reaction mixture was stirred for additional 5 hours at room temperature and the formed precipitate was removed by filtration. The solvent was evaporated under reduced pressure, and to the residue was added 50 ml of chloroform. The undissolved material was filtered off and the solution was dried over sodium sulfate. Addition of 10 ml of acetic acid to this solution followed by evaporation of the solvent gave a viscous oily product, which was reprecipitated with methanol-ethyl ether to afford 4-ethyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine acetate in a 62% yield.

    ______________________________________                                         Elemental analysis: as C.sub.24 H.sub.35 O.sub.7 N.sub.5 S                                  C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        55.01     7.28    12.34                                     Found   (%)        54.93     7.14    12.28                                     ______________________________________                                    

EXAMPLE 9

To a solution of 1.00 g (0.0041 mole) of 4-(L-arginyl) morpholine in 50 ml of chloroform and 0.52 g (0.0052 mole) of triethylamine was added 1.48 g (0.0052 mole) of 6,7-dimethoxy-2-naphthalenesulfonyl chloride with stirring at room temperature.

After stirring for 5 hours at room temperature, the reaction mixture was slurried with 10 ml of water.

The aqueous layer was separated, and the residual chloroform layer was dried over sodium sulfate. Addition of 2 ml of acetic acid to the chloroform layer followed by evaporation of chloroform gave a viscous oily residue, which was reprecipitated with methanol-ethyl ether to afford 4-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]morpholine acetate in a 66% yield.

    ______________________________________                                         Elemental analysis: as C.sub.21 H.sub.29 O.sub.8 N.sub.5 S                                  C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        52.07     6.37    12.65                                     Found   (%)        51.88     6.26    12.26                                     ______________________________________                                    

EXAMPLE 10

To a suspension of 1.0 g of N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 30 ml of ethanol was added little by little 1 ml of thionyl chloride with stirring. The suspension soon became a clear solution. After the solution was refluxed with stirring for 4 hours, the ethanol was distilled away under reduced pressure, to give a viscous oily residue, which was washed well three times with 20 ml of ethyl ether to afford colorless and powdery N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginine ethyl ester hydrochloride in a 96% yield.

    ______________________________________                                         Elemental analysis: as C.sub.20 H.sub.29 O.sub.6 N.sub.4 SCl                                C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        49.13     5.97    11.46                                     Found   (%)        48.96     6.15    11.52                                     ______________________________________                                    

EXAMPLE 11

A mixture of 1.0 g of N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of butyl alcohol and 30 ml of benzene was refluxed for 5 hours, while removing the water formed during the reaction. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl ether to yield a crystalline substance which was collected by filtration, washed several times with ethyl ether to afford N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate: yield 92%, m.p. 113°-115° C.

    ______________________________________                                         Elemental analysis: as C.sub.29 H.sub.40 O.sub.9 N.sub.4 S.sub.2                            C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        53.36     6.18    8.59                                      Found   (%)        53.23     6.14    8.70                                      ______________________________________                                    

EXAMPLE 12

To 1.2 g (0.0020 mole) of 4-ethyl-1-[N^(G) -nitro-N² -(6-chromansulfonyl)-L-arginyl]piperidine was added 0.64 g (0.0060 mole) of anisole and 3 ml of hydrogen fluoride while cooling with Dry-ice/acetone, and the mixture was stirred for 30 minutes in an ice bath. The excess hydrogen fluoride was evaporated at reduced pressure with cooling to afford an oily product, which was slurried with 100 ml of dry ethyl ether. The ether layer was separated by decantation, and the obtained powder was dissolved in methanol, reprecipitated with ethyl ether, and then filtered to give 4-ethyl-1-[N² -(6-chromansulfonyl)-L-arginyl]piperidine hydrofluoride in the powder form in a yield of 63%.

    ______________________________________                                         Elemental analysis: as C.sub.22 H.sub.36 O.sub.4 N.sub.5 S . HF                             C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        54.41     7.47    14.42                                     Found   (%)        54.70     7.45    14.31                                     ______________________________________                                    

EXAMPLE 13

Into a suspension of 1.2 g (0.0020 mole) of 4-ethyl-1-[N^(G) -nitro-N² -(1,4-benzodioxane-6-sulfonyl)-L-arginyl] piperidine and 0.1 g of palladium black in 30 ml of ethanol and 10 ml of acetic acid was passed hydrogen gas for 30 hours at room temperature. Upon completion of the reaction, the catalyst was filtered off, and the solvent was evaporated under reduced pressure to give a viscous oily residue, which was taken up in methanol and reprecipitated with ethyl ether to afford 4-ethyl-1-[N² -(1,4-benzodioxane-6-sulfonyl)-L-arginyl)piperidine acetate in the powder form in a yield of 85%.

    ______________________________________                                         Elemental analysis: as C.sub.21 H.sub.33 O.sub.5 N.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        52.35     7.07    13.27                                     Found   (%)        52.65     7.01    13.12                                     ______________________________________                                    

EXAMPLE 14

Into a suspension of 2.0 g (0.0026 mole) of 4-ethyl-1-[N^(G),N^(G) -dibenzyloxycarbonyl-N² -(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl]piperidine and 10% palladium-carbon in 50 ml of ethanol and 10 ml of acetic acid was passed hydrogen gas for 10 hours at room temperature. Upon completion of the reaction, the catalyst was filtered off, and the solvent was evaporated under reduced pressure to give a viscous oily residue, which was reprecipitated with methanol-ether to give 4-ethyl-1-[N² -(2H-3,4-dihydro-1,5-benzodioxepin-7-sulfonyl)-L-arginyl]piperidine acetate in the powder form in a yield of 81%.

    ______________________________________                                         Elemental analysis: as C.sub.24 H.sub.39 O.sub.7 N.sub.5 S . CH.sub.3          COOH                                                                                        C       H         N                                               ______________________________________                                         Calculated                                                                             (%)        53.22     7.26    12.93                                     Found   (%)        53.51     7.04    12.87                                     ______________________________________                                    

Various other N² -substituted-L-arginine esters and amides were synthesized in accordance with the procedures of the above examples. The results, including those of the above examples, are summarized in Table 1. In TABLE 1, N² -substituted-L-arginine esters and amides represented by the general formula (I) are shown by indicating R and R' in the formula and addition moieties.

                                      TABLE 1                                      __________________________________________________________________________      ##STR36##                  Addition                                                                              factor of twotime by                                                          acoagulationprolong therequired                                                totrationConcen-                                                                       (Ex.processtionpara-Pre-                                                           m.p.orProperty                                                                      Lower:                                                                        FoundCalculatedUpper:ele                                                       mental                                                                                   (KBr)I.R.          No.                                                                               R            R'         moiety (μM)                                                                               No.)                                                                               (° C)                                                                        C  H  N  (cm.sup.-1)         __________________________________________________________________________     1  O-n-C.sub.3 H.sub.7                                                                          ##STR37##                                                                                 ##STR38##                                                                            1.0    11  130 - 133                                                                           52.66 52.57                                                                       6.00 5.89                                                                         8.77 8.66              2  O-n-C.sub.4 H.sub.9                                                                          ##STR39##                                                                                 ##STR40##                                                                            0.2    7   113 - 115                                                                           53.36 53.23                                                                       6.18 6.14                                                                         8.59 8.70              3  O-n-C.sub.6 H.sub.13                                                                         ##STR41##                                                                                 ##STR42##                                                                            0.6    11  107 - 112                                                                           54.70 54.83                                                                       6.51 6.40                                                                         8.23 8.29                  ##STR43##                                                                                   ##STR44##                                                                                 ##STR45##                                                                            0.35   11  powder                                                                              55.48 55.36                                                                       5.53 5.29                                                                         8.09 8.19              5  OCH.sub.2 CH.sub.2 CH.sub.2 Cl                                                               ##STR46##                                                                                 ##STR47##                                                                            0.15   11  100 - 105                                                                           49.96 49.89                                                                       5.54 5.39                                                                         8.32 8.49              6                                                                                  ##STR48##                                                                                   ##STR49##                                                                                 ##STR50##                                                                            15     11  125 - 130                                                                           54.86 54.69                                                                       6.24 6.22                                                                         8.25 8.31              7  OCH.sub.2 CH.sub.2 OCH.sub.3                                                                 ##STR51##                                                                                 ##STR52##                                                                            0.25   11  104 - 107                                                                           51.37 51.44                                                                       5.85 5.76                                                                         8.56 8.57              8  OCH.sub.2 CH.sub.2 CCH                                                                       ##STR53##                                                                                 ##STR54##                                                                            1.5    11  127 - 131                                                                           53.69 53.54                                                                       5.59 5.32                                                                         8.64 8.46              9  OCH.sub.2 CHCHCH.sub.3                                                                       ##STR55##                                                                                 ##STR56##                                                                            1.5    11  powder                                                                              53.53 53.29                                                                       5.88 5.97                                                                         8.61 8.69              10 O-n-C.sub.4 H.sub.9                                                                          ##STR57##                                                                                 ##STR58##                                                                            50     11  94-98                                                                               54.70 54.66                                                                       6.51 6.42                                                                         8.23 8.53              11 OCH.sub.2 CH.sub.2 OCH.sub.3                                                                 ##STR59##                                                                                 ##STR60##                                                                            25<    11  100-105                                                                             51.42 51.51                                                                       6.32 6.54                                                                         7.99 8.02              12 OCH.sub.2 CHCHCH.sub.3                                                                       ##STR61##                                                                                 ##STR62##                                                                            4.5    11  powder                                                                              54.86 54.98                                                                       6.24 6.12                                                                         8.25 8.30              13  O-n-C.sub.4 H.sub.9                                                                         ##STR63##                                                                                 ##STR64##                                                                            5.5    11  148-151                                                                             53.36 53.50                                                                       6.18 6.20                                                                         8.59 8.60              14                                                                                 ##STR65##                                                                                   ##STR66## CH.sub.3 COOH                                                                         0.15   4   powder                                                                              55.21 55.11                                                                       6.95 6.74                                                                         12.38 12.01                                                                       3,300 (broad)                                                                  1,635               15                                                                                 ##STR67##                                                                                   ##STR68## CH.sub.3 COOH                                                                         0.15   8   powder                                                                              55.01 54.93                                                                       7.28 7.14                                                                         12.34  12.28                                                                      3,380 3,180                                                                    1,635               16                                                                                 ##STR69##                                                                                   ##STR70## HF     0.15   1   powder                                                                              55.64 55.50                                                                       7.10 7.12                                                                         12.98 12.87            17                                                                                 ##STR71##                                                                                   ##STR72## CH.sub.3 COOH                                                                         0.55   2   powder                                                                              55.21 55.04                                                                       6.95 6.78                                                                         12.38 12.26            18                                                                                 ##STR73##                                                                                   ##STR74## CH.sub.3 COOH                                                                         1.5    9   powder                                                                              52.07 51.88                                                                       6.37 6.26                                                                         12.65 12.26                                                                       3,360 3,180                                                                    1,640               19                                                                                 ##STR75##                                                                                   ##STR76## CH.sub.3 COOH                                                                         0.60   2   powder                                                                              53.69 53.48                                                                       6.72 6.68                                                                         12.04 12.00            20                                                                                 ##STR77##                                                                                   ##STR78## 2CH.sub.3 COOH                                                                        4.0    2   powder                                                                              51.75 51.49                                                                       6.76 6.39                                                                         13.41 13.21                                                                       3,400 3,200                                                                    1,640               21                                                                                 ##STR79##                                                                                   ##STR80## 2HF    4.0    1   powder                                                                              50.54 50.48                                                                       6.64 6.21                                                                         15.37 15.28            22                                                                                 ##STR81##                                                                                   ##STR82## CH.sub.3 COOH                                                                         1.5    3   powder                                                                              52.51 52.40                                                                       6.44 6.39                                                                         14.13 14.09            23                                                                                 ##STR83##                                                                                   ##STR84## CH.sub.3 COOH 3   powder                                                                              53.42 53.39                                                                       6.91 6.72                                                                         12.98 12.73                                                                       3,380 1,650         24                                                                                 ##STR85##                                                                                   ##STR86## CH.sub.3 COOH                                                                         0.5    5   powder                                                                              51.01 50.87                                                                       6.51 6.43                                                                         12.93 12.81                                                                       3,300 (broad)                                                                  1,640               25                                                                                 ##STR87##                                                                                   ##STR88## CH.sub.3 COOH                                                                         7.0    5   powder                                                                              50.60 51.00                                                                       6.19 6.21                                                                         12.30 12.28                                                                       3,400 3,200                                                                    1,740 1,665         26                                                                                 ##STR89##                                                                                   ##STR90## CH.sub.3 COOH                                                                         7.0    5   powder                                                                              51.45 51.37                                                                       6.39 6.26                                                                         12.00 11.69                                                                       3,200 (broad)                                                                  1,720 1,640                                                                    (broad)             27                                                                                 ##STR91##                                                                                   ##STR92## CH.sub.3 COOH                                                                         10     3   powder                                                                              56.14 56.01                                                                       6.81 6.46                                                                         12.13 12.00                                                                       3,300 (broad)                                                                  1,635               28                                                                                 ##STR93##                                                                                   ##STR94## CH.sub.3 COOH                                                                         7.0    3   powder                                                                              52.25 52.21                                                                       6.58 6.48                                                                         11.72 11.56            29                                                                                 ##STR95##                                                                                   ##STR96## CH.sub.3 COOH                                                                         7.0    3   powder                                                                              53.02 52.67                                                                       6.76 6.41                                                                         11.45 11.04            30                                                                                 ##STR97##                                                                                   ##STR98## CH.sub.3 COOH                                                                         30     3   powder                                                                              55.75 55.81                                                                       7.45 7.22                                                                         12.04 12.34                                                                       3,360 1,630                                                                    1,260 1,140         31                                                                                 ##STR99##                                                                                   ##STR100##                                                                               CH.sub.3 COOH                                                                         8.5    3   powder                                                                              56.64 56.51                                                                       7.70 7.65                                                                         11.80 11.98                                                                       3,350 1,640                                                                    1,260 1,160         32                                                                                 ##STR101##                                                                                  ##STR102##                                                                               CH.sub.3 COOH                                                                         0.075  3   powder                                                                              55.21 54.93                                                                       6.95 6.73                                                                         12.38 12.15            33                                                                                 ##STR103##                                                                                  ##STR104##                                                                               CH.sub.3 COOH                                                                         0.10   3   powder                                                                              55.01 54.84                                                                       7.28 7.16                                                                         12.34 12.03            34                                                                                 ##STR105##                                                                                  ##STR106##                                                                               CH.sub.3 COOH                                                                         5.5    3   powder                                                                              57.31 57.55                                                                       7.46 7.71                                                                         11.52 11.32                                                                       3,350 1,680                                                                    1,160               35                                                                                 ##STR107##                                                                                  ##STR108##                                                                               CH.sub.3 COOH                                                                         0.8    3   powder                                                                               56.73 56.75                                                                      5.82 5.71                                                                         12.25 11.98                                                                       3,350 1,650                                                                    1,150               36                                                                                 ##STR109##                                                                                  ##STR110##                                                                               HF     15     12  powder                                                                              54.41 54.70                                                                       7.47 7.45                                                                         14.42 14.31                                                                       3,300 (broad)                                                                  1,640               37                                                                                 ##STR111##                                                                                  ##STR112##                                                                               CH.sub.3 COOH                                                                         25     13  powder                                                                              52.35 52.65                                                                       7.07 7.01                                                                         13.27 13.12                                                                       3,320 1,640         38                                                                                 ##STR113##                                                                                  ##STR114##                                                                               CH.sub.3 COOH                                                                         5      14  powder                                                                              53.22 53.51                                                                       7.26 7.04                                                                         12.93 12.87                                                                       3,350 (broad)                                                                  1,635               39                                                                                 ##STR115##                                                                                  ##STR116##                                                                               CH.sub.3 COOH                                                                         8      13  powder                                                                              52.35 52.60                                                                       7.07 6.95                                                                         13.27 13.40                                                                       3,100 (broad)                                                                  1,640               40                                                                                 ##STR117##                                                                                  ##STR118##                                                                               CH.sub.3 COOH                                                                         25     14  powder                                                                              48.92 49.21                                                                       6.45 6.45                                                                         13.58 13.41                                                                       3,400 3,180                                                                    1,640               41                                                                                 ##STR119##                                                                                  ##STR120##                                                                               CH.sub.3 COOH                                                                         100    13  powder                                                                              51.25 51.53                                                                       7.23 7.46                                                                         13.58 13.29                                                                       3,350 1,640                                                                    1,280               42                                                                                 ##STR121##                                                                                  ##STR122##                                                                               --     6      13  powder                                                                              53.99 53.75                                                                       7.29 7.61                                                                         13.69 13.50                                                                       3,400 1,630         43                                                                                 ##STR123##                                                                                  ##STR124##                                                                               CH.sub.3 COOH                                                                         0.3    13  powder                                                                              58.62 58.32                                                                       6.85 6.58                                                                         12.21 11.99                                                                       3,340 1,630                                                                    1,265               44                                                                                 ##STR125##                                                                                  ##STR126##                                                                               1/2H.sub.2 O                                                                          0.3    13  powder                                                                              59.03                                                                             6.54 6.48                                                                         13.77 13.63                                                                       3,350 1,630                                                                    1,275               45                                                                                 ##STR127##                                                                                  ##STR128##                                                                               CH.sub.3 COOH                                                                         0.2    13  powder                                                                              57.94 57.64                                                                       6.66 6.65                                                                         12.51 12.24                                                                       3,350 1,630                                                                    1,160               46                                                                                 ##STR129##                                                                                  ##STR130##                                                                               CH.sub.3 COOH                                                                         0.15   13  powder                                                                              56.33 56.08                                                                       6.48 6.45                                                                         12.17 11.96                                                                       3,300 1,630                                                                    1,290               47                                                                                 ##STR131##                                                                                  ##STR132##                                                                               CH.sub.3 COOH                                                                         0.5    13  powder                                                                              57.23 57.01                                                                       6.47 6.41                                                                         12.84 12.61                                                                       3,350 1,635                                                                    1,270               48                                                                                 ##STR133##                                                                                  ##STR134##                                                                               CH.sub.3 COOH                                                                         5      13  powder                                                                              57.02 56.74                                                                       6.81 6.93                                                                         12.79 12.65                                                                       3,310 1,640                                                                    1,260               __________________________________________________________________________ 

What is claimed as new and intended to be covered by letters patent is:
 1. N² -substituted-L-arginine esters and amides having the formula: ##STR135## and the pharmaceutically acceptable acid addition salts thereof, wherein R is selected from the group consisting of (1) --OR₁, wherein R₁ is selected from the group consisting of C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl, C₁ -C₁₀ haloalkyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl and C₇ -C₁₅ aralkyl, ##STR136## wherein R₂ and R₃ are selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₅ aralkyl, and C₁ C₁₀ alkyl substituted with a group selected from C₁ -C₁₀ alkoxy, C₂ -C₁₀ alkoxycarbonyl and carboxy; and (3) -N Z, wherein Z is a divalent group which consists of at least two groups selected from methylene --CH₂ -- and monosubstituted ##STR137## wherein R₄ is selected from the group consisting of C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy, which are combined in an arbitrary order, the number of the combined groups being up to 20; and R' is selected from the group consisting of ##STR138## wherein R" and R'" when considered separately are C₁ -C₁₀ alkyl, or R" and R'" when taken together are C₁ -C₁₀ alkylene; ##STR139## wherein R"" is C₁ -C₁₀ alkoxy; ##STR140##
 2. The compounds of claim 1, wherein R is --OR₁ wherein R₁ is selected from the group consisting of C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl, C₁ -C₁₀ haloalkyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl and C₇ -C₁₅ aralkyl; and R' is ##STR141## wherein R" and R'" when considered separately are C₁ -C₁₀ alkyl, or R" and R'" when taken together are C₁ -C₁₀ alkylene.
 3. The compounds of claim 2, wherein R is selected from the group consisting of C₁ -C₈ alkoxy, cyclohexyloxy, C₂ -C₆ omega-chloroalkoxy, C₂ -C₆ omega-alkoxyalkoxy, C₃ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy and C₇ -C₉ aralkyloxy; and R' is ##STR142## wherein R" and R'" when considered separately are C₁ -C₅ alkyl, or R" and R'" when taken together are C₁ -C₅ alkylene.
 4. The compounds of claim 3, wherein R is selected from the group consisting of propoxy, butoxy, hexyloxy, cyclohexyloxy, 3-chloropropoxy, 2-methoxyethoxy, 2-butenyloxy, 3-butynyloxy and benzyloxy; and R' is selected from the group consisting of ##STR143##
 5. The compounds of claim 1, wherein R is ##STR144## wherein R₂ and R₃ are selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₅ aralkyl, and C₁ -C₁₀ alkyl substituted with a group selected from C₁ -C₁₀ alkoxy, C₂ -C₁₀ alkoxycarbonyl and carboxy.
 6. The compound of claim 5, wherein R is selected from the group consisting of C₁ -C₉ alkylamino, C₂ -C₆ omega-alkoxyalkylamino, C₃ -C₈ omega-alkoxycarbonylalkylamino, C₇ -C₁₀ aralkylamino and C₂ -C₁₀ dialkylamino; and R' is selected from the group consisting of ##STR145## wherein R" and R'" when considered separately are C₁ -C₅ alkyl, or R" and R'" when taken together are C₁ -C₅ alkylene; ##STR146## wherein R"" is C₁ -C₅ alkoxy, ##STR147##
 7. The compound of claim 6, wherein R is selected from the group consisting of butylamino, 2-methoxyethylamino, 2-methoxycarbonylethylamino, 2-ethoxycarbonylethylamino, benzylamino and N-methyl-N-butylamino; R' is selected from the group consisting of ##STR148##
 8. The compounds of claim 1, wherein R is -N Z, wherein Z is a divalent group which consists of at least two groups selected from methylene --CH₂ -- and monosubstituted ##STR149## wherein R₄ is selected from the group consisting of C₁ -C₁₀ alkyl and C₁ -C₁₀ akoxy, which are combined in an arbitrary order, the number of the combined groups being up to
 20. 9. The compounds of claim 8, wherein R is selected from the group consisting of C₃ -C₁₀ N,N-polymethyleneiminyl; and C₃ -C₁₀ N,N-polymethyleneiminyl substituted with a group selected from the group consisting of C₁ -C₅ alkyl and C₁ -C₅ alkoxy; and R' is selected from the group consisting of ##STR150## wherein R' and R'" when considered separately are C₁ -C₅ alkyl, or R" and R'" when taken together are C₁ -C₅ alkylene; ##STR151## wherein R"" is C₁ -C₅ alkoxy; ##STR152##
 10. The compounds of claim 9, wherein R is selected from the group consisting of piperidino, hexamethyleneiminyl, 4-methylpiperidino, 4-ethylpiperidino and 4-methoxypiperidino; and R' is selected from the group consisting of ##STR153##
 11. A compound of claim 4, which is N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester.
 12. A compound of claim 7, which is N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-N-(2-methoxyethyl)-L-argininamide.
 13. A compound of claim 10, which is 4-methyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine.
 14. A compound of claim 10, which is 4-ethyl-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine.
 15. A compound of claim 10, which is 4-methoxy-1-[N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine.
 16. A compound of claim 10, which is 4-methyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine.
 17. A compound of claim 10, which is 4-ethyl-1-[N² -(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl]piperidine.
 18. A compound of claim 10, which is 4-ethyl-1-[N² -(2-xanthenesulfonyl)-L-arginyl]piperidine.
 19. A compound of claim 10, which is 4-ethyl-1-[N² -(4-dibenzofuransulfonyl)-L-arginyl]piperidine.
 20. A compound of claim 10, which is 4-ethyl-1-[N² -(dibenzo-p-dioxin-2-sulfonyl)-L-arginyl]piperidine.
 21. A pharmaceutical composition which comprises an amount of a compound of claim 1, effective for inhibiting activity and suppressing activation of thrombin in vivo, and a pharmaceutically acceptable carrier.
 22. A method for inhibiting activity and suppressing activation of thrombin in vivo, which comprises administering to a patient a pharmaceutically effective amount of an N² -substituted-L-arginine ester or amide having the formula: ##STR154## or a pharmaceutically acceptable acid addition salt thereof, wherein R is selected from the group consisting of (1) --OR₁, wherein R₁ is selected from the group consisting of C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl, C₁ -C₁₀ haloalkyl, C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl and C₇ -C₁₅ aralkyl; ##STR155## wherein R₂ and R₃ are selected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₅ aralkyl, and C₁ -C₁₀ alkyl substituted with a group selected from C₁ -C₁₀ alkoxy, C₂ -C₁₀ alkoxycarbonyl and carboxy; and (3) -N Z, wherein Z is a divalent group which consists of at least two groups selected from the group consisting of methylene --CH₂ -- and monosubstituted ##STR156## wherein R₄ is selected from the group consisting of C₁ -C₁₀ alkyl and C₁ -C₁₀ alkoxy, which are combined in an arbitraary order, the number of the combined groups being up to 20; and R' is selected from the group consisting of ##STR157## wherein R" and R'" when considered separately are C₁ -C₁₀ alkyl, or R" and R'" when taken together are C₁ -C₁₀ alkylene; ##STR158## wherein R"" is C₁ -C₁₀ alkoxy; ##STR159## 